Alzheimer's disease (AD) is the most common cause of dementia in the elderly and affects millions of people worldwide. AD pathology includes characteristic amyloid plaques and neurofibrillary tangles composed of tau and at later stages synaptic loss and significant neurodegeneration. Major symptoms of AD, including memory loss and cognitive decline, correlate closely in their severity to the degree of neuronal loss an individual experiences. Previous work from our lab and others has proposed that nuclear receptors are important players in the clearance of amyloid pathology and inflammation in AD mouse models, but the role of NRs in neurodegeneration has not yet been addressed. The NR4A subfamily of NRs are known to have neuroprotective effects, and dysregulation of NR4A family members Nurr1 (NR4A2) and Nur77 (NR4A1) is implicated in Parkinson's disease and other neurodegenerative disorders. The hypothesis driving this proposal is that NR4A dysregulation is a key component of neurodegeneration in AD and that decreasing NR4A expression will have a direct impact on neuronal survival. One specific goal of this proposal is to determine if NR4A expression changes with pathological progression in a mouse model of AD. This problem will be addressed using the 5XFAD, a mouse model of AD that exhibits significant neuronal loss, especially in the hippocampus and layers V/VI of the cortex. Animals will be assessed for overall NR4A expression at different stages of neurodegeneration, and cell- type specific levels of NR4As in neurons, microglia, and astrocytes will be evaluated to determine contributing cell types. A second specific goal of this proposal is to determine if the deletion of NR4A receptors exacerbates neuronal death in an AD model. 5XFAD mice will be crossed to mice conditionally null for Nurr1 and assessed for changes in severity and time of onset of neuronal death. NR4A expression will also be stimulated in the 5XFAD mouse using pharmacological agents such as the RXR agonist bexarotene to determine if NR4As provide a potential therapeutic target for treating AD-related neurodegeneration. Characterizing the role of NR4A family NRs in AD will allow for a better understanding of the mechanisms of neuronal loss, and could provide a novel target for therapeutic treatment of AD.